The role of oxidative stress in periodontitis

Jou nal o Pe iodon al Resea ch, 2025; 0:1–22
h ps://doi.o g/10.1111/j e.70016
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Jou nal o Pe iodon al Resea ch
NARRATIVE REVIEW OPEN ACCESS
The Role o Oxida i e S ess in Pe iodon i is
Ped oBullon1 | F ancescaGiampie i2,3,4,5 | Bea izBullon1 | Mau izioBa ino2,3,4,5
1Depa men o S oma ology, Den al School, Uni e sidad de Se illa, Se illa, Spain | 2Join Labo a o y on Food Science, Nu i ion, and In elligen
P ocessing o Foods, Uni e si à Poli ecnica Delle Ma che, Ancona, I aly | 3Uni e sidad Eu opea del A lan ico, San ande , Spain | 4Depa men o Clinical
Sciences, Uni e si à Poli ecnica Delle Ma che, Ancona, I aly | 5Resea ch G oup on Food, Nu i ional Biochemis y and Heal h, Uni e sidad Eu opea del
A lán ico, San ande ,Spain
Co espondence: Ped o Bullon ([email protected])
Recei ed: 22 Ma ch 2025 | Re ised: 12 June 2025 | Accep ed: 16 June 2025
Keywo ds: an ioxidan s| in lamma ion| oxida i e s ess| pe iodon i is| pe sonalized he apy
ABSTRACT
Pe iodon i is and noncommunicable diseases sha e an o e all in lamma o y s a e o en sus ained by concomi an oxida i e
s ess as one o he main p ocesses in ol ed. A huge amoun o li e a u e suppo s such a main pa hogenic p ocess, which is
also conside ed he he apeu ic a ge . The a emp o con ol in lamma ion by ac ing on oxida i e s ess has gi en la gely un-
sa is ac o y esul s, ei he as p e en i e o as ea men app oaches. To p opose new ideas ha will help in his ield, he pape
e iewed all physiological p ocesses in ol ed in oxida i e s ess in pe iodon i is. The discussion conside s all o hem, consid-
e ing whe he hey come om endogenous sou ces, ha is, all he in acellula physiological de ices and/o p ocesses ha a e
in ol ed in oxida i e s ess, such as mi ochond ia, ough endoplasmic e iculum, pe oxisomes, au ophagy, and aging, o om
exogenous sou ces, ha is, he ex e nal ac o s ha a ec oxida i e s ess, such as nu i ion, physical ac i i y, psychological s a-
us, en i onmen al condi ions, mic obiome, and d ugs. The mos impo an conclusion is ha all o hem should be aken in o
conside a ion in u u e esea ch since we need o add ess oxida i e s ess as pa o a speci ic biological and me abolic cellula
s a e in a mul icellula o ganism. To unde s and he cellula physiology ha unde lies oxida i e s ess and conside his poin
in ea ing each o ou pe iodon al pa ien s acco ding o a speci ic oxida i e s a e could be called pe sonalized/p ecise oxida i e
s ess he apy (POST) and should include he ollowing poin s: (1) en i onmen al condi ions, (2) indi idual cha ac e is ics, and
(3) oxida i e s a e o di e en in acellula o ganelles.
1 | In oduc ion
The pa hogenesis o pe iodon i is p esen s mo e ques ions han
ce ain ies. The main ole o bac e ia, and he concep o dysbi-
osis as an imbalance o dis up ion o he o al bac e ial commu-
ni y, a e well es ablished. Howe e , he abo e canno ho oughly
explain all he aspec s. Bac e ial in ec ion p oduces a eac ion
in all mul icellula o ganisms, which is a de ense mechanism:
in lamma ion. I ies o elimina e he bac e ia, isola e he dam-
aged issue, and eco e wi h issue egene a ion. In lamma ion
in ol es mul iple me abolic and molecula mechanisms ha
depend on he cha ac e is ics and sys emic heal h o he hos
o ganisms. When his eac ion is exace ba ed o educed, many
diseases can occu . Sys emic in lamma ion is he main mech-
anism behind disease onse , such as ca dio ascula diseases,
Type 2 diabe es, cance s, and pe iodon i is among o he s. All
hese diseases a e g ouped in he so- called noncommunicable
diseases ha kill 41 million people each yea , equi alen o 74%
o all dea hs globally [1].
One o he main p ocesses, gi ing ise o in lamma ion, in ol ed
in all hese diseases is oxida i e s ess (OS).
A huge amoun o li e a u e deals wi h OS as a main pa hogenic
p ocess and he apeu ic a ge o all in lamma o y diseases
and, o cou se, o pe iodon i is. The esul s behind he e o o
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© 2025 The Au ho (s). Jou nal o Pe iodon al Resea ch published by John Wiley & Sons L d.
2 o 22 Jou nal o Pe iodon al Resea ch, 2025
con ol in lamma ion ha e been la gely unsuccess ul ei he as a
p e en i e o a cu a i e measu e. The eason is ha we need o
know wha is behind he concep o OS and he ela ionship wi h
cellula physiology. Acco ding o he Na ional Cance Ins i u e
[2] OS is de ined as: “A condi ion ha may occu when he e
a e oo many uns able molecules called ee adicals (FR) in he
body and no enough an ioxidan s o ge id o hem. This can
lead o cell and issue damage.” This concep includes an equi-
lib ium be ween he p oduc ion o FR, bu also eac i e oxygen/
ni ogen species (ROS/RNS) and he p esence o an ioxidan
mechanisms ha y o con ol i .
FR, ROS, and RNS can damage molecula cellula compo-
nen s. To coun e ac his ac ion, an ioxidan s a e in ol ed.
An ioxidan s a e any subs ance ha signi ican ly delays o p e-
en s oxida ion o he subs a e. Th ee kinds o an ioxidan s
exis : (i) p e en i e an ioxidan s, (ii) adical sca enge s, (iii)
epai and de no o enzymes [3]. Redox p ocesses ake place in
all bioene ge ics p ocesses, me abolism and li e unc ions: hey
a e in ol ed in pH con ol, phospho yla ion–dephospho yla ion
eac ion, ace yla ion/deace yla ion, and in me hyla ion/deme h-
yla ion, as well as in cen al mechanisms o con olling he ge-
nome and epigenome [4].
Oxygen, he mos success ul oxida i e molecules, is used in all
ae obic o ganisms o p oduce ene gy wi h he oxida ion o nu-
ien s ich in ca bon and hyd ogen. In con as , an anae obic
o ganism does no equi e oxygen; cellula espi a ion u ilizes
elec on accep o s such as ino ganic compounds (e.g., hyd ogen
gas, hyd ogen sul ide) o e ous ions as a sou ce o ene gy. The
i s o m o li e, known as he las uni e sal common ances o
(LUCA), is he node on he ee o li e whe e he di e en do-
mains o li e di e ge. Th ough phylogene ic econcilia ion me h-
ods, LUCA has been demons a ed o be a p oka yo e- g ade
anae obic ace ogen ha possessed an ea ly immune sys em and
used ATP as a common ene gy cu ency [5]. I is hough ha i
appea ed in he absence o ligh and oxygen in he hyd o he -
mal en s o he sea loo . La ely, his way o anae obic li ing
s a ed o p oduce oxygen ha is oxic, bu some bac e ia used
i due o a mos e icien way o p oduce ene gy. Anae obic me-
abolism p oduces ou ATP molecules om one glucose mole-
cule, and ae obic me abolism p oduces 34 ATP molecules. This
ene gy p oduc ion akes place wi h i e g oups o p o eins ha
cons i u e he elec on anspo chain embedded in he inne
mi ochond ial memb ane. A ans e o elec ons om elec on
dono s o elec on accep o s ia edox eac ion akes place o-
ge he wi h a concomi an ansloca ion agains he g adien
o p o ons (H+, hyd ogen ions) ac oss he memb ane and cou-
ples he ollowing phenomenon o g adien dissipa ion h ough
ATPase o p oduce ATP om ADP.
Howe e , cells use his oxida i e eac ion no only o p oduce
ene gy bu also as a de ense mechanism. Bac e ia, mainly in he
endocy osis p ocess, a e engul ed by he plasma memb ane and
gi e ise o phagosomes ha a e linked o he lysosome and de-
g aded. I akes place mainly in neu ophils and mac ophages.
These lysosomes con ain many hyd oly ic enzymes: p o eases,
nucleases, and phospha ases wi h hei maximum enzyma ic
ac i i y a a low pH (pH ≤ 5) ha deg ades bac e ia [6]. The
ini ial p oduc o NADPH oxidase ha causes his espi a o y
bu s in leukocy es is supe oxide, which is eleased by he oxi-
da ion o educed nico inamide adenine dinucleo ide phospha e
(NADPH). ROS p oduc ion is pa o he neu ophil de ense
mechanism, and i s hype esponsi eness is ela ed o pe iodon-
i is [7].
Cells no only use his deg ada ion p ocess as a de ense de ice
agains bac e ia bu also o con ol dys unc ional cellula com-
ponen s by deg ading hem in a p ocess called au ophagy. In
addi ion, some oxidan s can ac as a edox second messenge in
edox biology and as a signal o gene exp ession. Fo ins ance,
hyd ogen pe oxide (H2O2), an uncha ged oxidan molecule, is
well sui ed o edox sensing and edox signaling [8], eac i e
sul ide species a e p e alen in in acellula edox signaling [9],
and ni ic oxide, a gaseous signaling molecule, is a key egula o
o ca dio ascula unc ion [10] (Box1).
Many pape s, including sys ema ic e iews and me a- analyses,
ha e s udied he ole o oxida i e s ess in he pa hogenesis o in-
lamma o y diseases and he ea men o pe iodon i is, sugges -
ing some imes ea ing pe iodon i is as an in lamma o y disease
wi h oxida i e s ess as he a ge and using, o example, es e -
a ol and cu cumin as he apeu ic an ioxidan agen s in conjunc-
ion wi h con en ional he apies [11]. Howe e , scien i ic esea ch
has no ye been able o implemen any ype o an ioxidan ea -
men in pe iodon al he apy. In ou opinion, a new app oach is
needed. The adminis a ion o an an ioxidan canno be based on
he same p inciple as he adminis a ion o a i amin, enzyme, o
ho mone when hese a e lacking in he body. I is known ha in
ce ain diseases caused by hei de iciency, he adminis a ion o
hese p oduc s achie es a cu e.
The objec i e o his na a i e e iew was o highligh he cel-
lula mechanisms ha unde lie hese aspec s and could p o ide
clues ha may in o m u u e esea ch. Oxida i e s ess is a bal-
ance de i ed om ae obic me abolism, which is pa o cellula
homeos asis. I an excessi e numbe o an ioxidan s a e p o ided,
hei ac ion can in e e e wi h ene gy p oduc ion o de ense
mechanisms o signaling. Redox p ocesses depend on he ype o
Summa y
• Oxida i e s ess in ol es mul iple p ocesses ha
should be known and conside ed as pa o a he a-
peu ic s a egy.
BOX 1 | Oxida i e s ess.
• Oxida i e s ess can occu when he e a e oo many un-
s able molecules called ee adicals (FR) in he body and
no enough an ioxidan s o elimina e hem [2].
• An ioxidan s a e any subs ance ha signi ican ly delays
o p e en s oxida ion o he subs a e [3].
• Redox p ocesses ake place in all bioene ge ic p ocesses,
me abolism, and li e unc ions [4].
• The oxida i e eac ion p oduces ene gy, is pa o he
de ense mechanism, and is in ol ed in he deg ada ion
p ocess [6].
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speci ic cell, issue, o o gan. The op imal pH a ies acco ding o
he cellula o subcellula space, and he e is an op imal pa e n
o p o- oxidan s and an ioxidan s o each physiological p ocess.
This way o hinking is he basis o he concep o pe sonalized/
p ecision medicine: Diagnos ic es ing employed o selec app o-
p ia e and op imal he apies based on he pa ien 's gene ics o
hei o he molecula o cellula cha ac e is ics [12, 13].
All hese aspec s should be highligh ed i we ea an in lam-
ma o y disease conside ing oxida i e s ess as he main a ge o
he he apeu ic app oach. All physiological p ocesses in ol ed
in oxida i e s ess ha e been e iewed. They a e analyzed, con-
side ing whe he hey o igina e om exogenous o endogenous
sou ces. The o me conside s all in acellula physiological p o-
cesses ha a e in ol ed in oxida i e s ess, while he la e a e
ex e nal ac o s ha a ec oxida i e s ess. All o ganisms a e
in luenced by he en i onmen and mus adap o all ex e nal
s imuli capable o modula ing hei cha ac e is ics and de e -
mining hei de e io a ion h ough oxida i e s ess (Box2).
2 | Endogenous Sou ces
2.1 | Mi ochond ia
We a e ae obic mul icellula o ganisms ha p oduce ene gy in
he mos p oduc i e way wi h oxygen ha oxidizes nu ien s in
a con olled bu ning p ocess. The whole p ocess akes place in
one o he mos impo an in acellula o ganelles, he mi o-
chond ion (Box3).
Ene gy p oduc ion, as he main cha ac e is ic o ou li ing
o m, has an impo an undesi able side e ec . The elec on
anspo chain p oduces ROS, mainly by Complex I and III
[14], con olled by an ioxidan mechanisms, bu some imes ox-
idan s a e o e p oduced, and an ioxidan s a e o e whelmed,
hus damaging di e en molecules and o ganelles and leading,
inally, o mi ochond ial dys unc ion and di e en diseases
[15]. Oxida i e s ess damages mi ochond ial s uc u es and
unc ion, dis up s mi ochond ial memb ane in eg i y ha
eleases damage- associa ed pa e ns (DAMPs), ac i a es he
pa e n ecogni ion ecep o s (PPRs) o he inna e immune
sys em, and igge s in lamma ion wi h he ac i a ion o he
in lammasome [28]. Mi ochond ia gene a e mos cellula ROS
and play a cen al ole in he egula ion o oxida i e s ess and
cellula edox homeos asis [16]. The e o e, he egula ion o in-
na e immuni y and in lamma o y esponses agains in ec ion
pa hogens is conside ed a cen al signaling hub o in eg a ion
and ansduc ion o he cell esponse [29], o egula ing he
inna e and adap i e immuni y [17], and communica ion wi h
dis an issues in a noncell- au onomous manne h ough di -
e en molecules [30]. Mac ophages, which elimina e mic oo -
ganisms by phagocy osis and play an impo an ole in inna e
and adap i e immuni y, p oduce eac i e mi ochond ial spe-
cies du ing Toll- like ecep o (TLR)- dependen in lamma o y
esponses ha igge mi oho mesis as a nega i e eedback
mechanism o es ic in lamma ion h ough ole ance [31].
Mi oho mesis is a mechanism in which exposu e o low doses
o ROS enhances sys emic de ense mechanisms by inducing an
adap i e esponse, in con as o high le els o ROS ha cause
cell damage [32].
BOX 2 | Endogenous and exogenous oxida i e sou ces.
Endogenous sou ces Exogenous sou ces
• Mi ochond ia
• Rough endoplasmic e iculum
• Pe oxisomes
• Au ophagy
• Aging
• Nu i ion
• Physical ac i i y
• Psychological s a us
• En i onmen al condi ions
• Mic obiome
• D ugs
BOX 3 | Essen ial aspec s o mi ochond ia.
Gene al aspec s Pe iodon al aspec s
• Essen ial o ganelles in oxida i e ene gy p oduc ion [14].
• Gene a e mos cellula ROS [15].
• Play a cen al ole in he egula ion o oxida i e s ess
and cellula edox homeos asis, as well as in acellula
calcium and apop osis [16].
• Rela ed o immuni y and in lamma ion [17].
• G ea adap a ion o ene gy demands [18].
• Con ain ci cula DNA [19].
• They o m a highly dynamic ne wo k [20].
• Mi ochond ial dys unc ion leads o an undesi able
in lamma o y esponse [21].
• Mi ochond ial dys unc ion is p esen in pe iodon i is [22].
• m DNA inc eases pe iodon i is suscep ibili y [23].
• Oxida i e s ess p oduces a ian s o m DNA in
pe iodon i is and ca dio ascula disease [24].
• Pe iodon al ea men dec eases mi ochond ial ROS
p oduc ion [25].
• P. gingi alis and F. nuclea um in luence mi ochond ia [26].
• Mi ochond ia p omo e issue egene a ion [27].
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4 o 22 Jou nal o Pe iodon al Resea ch, 2025
The mos impo an cha ac e is ic o mi ochond ia is hei abil-
i y o adap o ene gy demands. They a e highly dynamic and
can be emodeled in seconds [18]. The numbe o mi ochond ia
can a y om absence, as in ma u e ed blood cells, o hei
p esence in la ge quan i ies, as in li e cells (mo e han wo
housand), and hey can mig a e om one cell o ano he [33].
The coexis ence o se e al mi ochond ial subpopula ions has
been obse ed in di e en issues and e en wi hin he same cell
[34]. Mi ochond ia ha e o he essen ial unc ions o cell su -
i al, such as hea p oduc ion, a y acid syn hesis, calcium con-
cen a ions, p og ammed cell dea h, and inna e immuni y [35].
The con aining o ci cula DNA held he hypo hesis o an endo-
symbio ic o igin. Mi ochond ial DNA (m DNA) is dis inc om
he nucleus, as i has a lack o cy osine and guanine me hyla ion
[19]. The mi ochond ial ances o could ha e been a bac e ium o
an Asga d a chaeon (a g oup o uncul i a ed a chaea) engul ed
by a p o eobac e ium [36]. Then some po ions o m DNA we e
ans e ed o he cellula nucleus, maybe o p o ec hem om
a high oxida i e en i onmen ; he e o e, wo DNAs con ol he
mi ochond ial p o eins. A ound 1500 mammalian mi ochon-
d ial p o eins a e syn hesized om nuclea genes, and 13 om
m DNA [37]. Bo h a e ela ed; con inuous changes in m DNA
he e oplasmy esul in discon inuous emodeling o nuclea
DNA and m DNA gene exp ession p o iles due o al e a ions in
bo h he signal ansduc ion and epigene ic egula o y p ocesses
[38]. Ano he way o a oid he oxida i e en i onmen is wi h
con inuous eplica ion o m DNA wi h a hal - li e o 7–10 days
[39]. Oxidized m DNA is a key dange signal ha igge s s e ile
in lamma ion h ough ac i a ion o he NLRP3 in lammasome,
which has been linked o many ch onic diseases [40].
Mi ochond ia a e inhe i ed only om he mo he ; his leads
o he basis o s udying popula ion gene ics and e olu iona y
biology [41]. They o m a highly dynamic ne wo k ha unde -
goes cons an ission, usion, biogenesis, and au ophagy p o-
cesses acco ding o he needs o cellula me abolism. Fusion
mi iga es s ess and is s imula ed by ene gy demand, while
ission c ea es new mi ochond ia and acili a es quali y con-
ol [20]. Mi ochond ial ission and usion con ibu e o hei
unc ions and ROS p oduc ion [42]. Mi ochond ial p oduc ion
in ol es mul iple signals; one o hem is pe oxisome p oli e a o -
ac i a ed ecep o s (PPARs). I s genes and i s ac i a ion ha e
been associa ed wi h ypical bone loss om pe iodon i is and
could be a mee ing poin wi h me abolic diso de s [43].
Mi ochond ia also exis ou side cells in pla ele s, in ex acellula
esicles; also, a cell- ee ci cula ing mi ochond ial DNA exis s
[44]. Small ex a esicula esicles ha con ain espi a ion-
compe en bu oxida i ely damaged mi ochond ial pa icles can
en e he ci cula ion and p o ide mi ochond ial ans e be-
ween issues ha can es o e he me abolic ac i i y o cells wi h
impai ed me abolism [45].
In lamma ion includes complex mul i ace ed mechanisms, and
mi ochond ia a e in ol ed in he onse and de elopmen o in-
lamma o y condi ions. Mi ochond ial dys unc ion leads o an
undesi able in lamma o y esponse [21] and can cause sys emic
diso de s such as neu ological ones, bu also myopa hies, endo-
c inopa hies, and is ela ed o aging, oo. Genomic s udies ound
se e al associa ions be ween changes in m DNA and nuclea
mi ochond ial genes in ca diome abolic diseases [46]. m DNA
con ols he mi ochond ial p o ein machine y, and he link
> 40% o he mi ochond ial p o eome o human diseases has
been iden i ied [47].
In pe iodon i is, some da a p o ide some e idence o he e-
la ionship be ween pe iodon i is and mi ochond ia. Va ious
bac e ia and i uses can a ec mi ochond ial dynamics and
unc ions in hos cell me abolism and immune esponse as a
pa hogenic mechanism [48]. As an example o his e ec , some
s udies sugges ha mi ochond ial dys unc ion may be p esen
in pe iodon i is, linking i wi h sys emic diseases [22]. Recen
e iews showed an o e iew o he in e play be ween mi o-
chond ia and pe iodon i is [49–51]. Mo phome ic s udies in
gingi al ib oblas mi ochond ia om pa ien s wi h ca diac
disease showed a educed numbe and inc eased olume no -
malized by ni edipine and dil iazem [52]. Mi ochond ial s uc-
u e and unc ion o human gingi al ib oblas s a e impai ed
in pa ien s wi h ch onic pe iodon i is compa ed o heal hy pa-
ien s [53]. The mi ochond ial memb ane po en ial and oxygen
consump ion o gingi al cells we e educed and he m DNA
showed no el mu a ions [54]. In a Chinese popula ion, a signi -
ican associa ion was obse ed be ween agg essi e pe iodon-
i is and eigh m DNA polymo phisms, making pe iodon i is
suscep ibili y inc ease [23]. A o al o 162 unique a ian s in
he m DNA sequences we e desc ibed in pa ien s su e ing
om pe iodon i is and ca dio ascula disease, and 12 o hem
we e he esul o oxida i e s ess [24]. In an animal model,
mi ochond ial dys unc ion was posi i ely co ela ed wi h ag-
g a a ed pe iodon i is in diabe es [55]. In a andomized clin-
ical con ol s udy, in ensi e pe iodon al ea men ma kedly
dec eased mi ochond ial ROS p oduc ion in pa ien s wi h pe i-
odon i is and Type 2 diabe es [25].
Po phy omonas gingi alis can p omo e mi ochond ial ission
in endo helial cells wi h up egula ion o D p1 [56], educe he
exp ession o PINK1, a mi ophagy gene, and impai he clea -
ance o damaged mi ochond ia in mac ophages [57]. P. gingi-
alis and Fusobac e ium nuclea um egula e he exp ession o
mi ochond ia- ER con ac - ela ed genes ha a e pa o hos –mi-
c obiome in e ac ions [26]. The lipopolysaccha ide o P. gingi a-
lis in ib oblas s p oduces a dec ease in mi ochond ial p o ein
exp ession, mi ochond ial mass, and mi ochond ial memb ane
po en ial [58].
The ole o mi ochond ia in he egene a i e p ocess has also
been s udied. Induced plu ipo en s em cells ha e been applied
o egene a i e medicine, bu success depends on cellula mech-
anisms, which in u n depend on mi ochond ia o main ain plu-
ipo ency and de elop unc ional, di e en ia ed cell ypes [27].
Mesenchymal s em cells a e in ol ed due o angiogenic and
an iapop o ic unc ions, media ed by hei pa ac ine e ec s and
sha ing hei mi ochond ia wi h a ge cells [59]. Pla ele s a e
used in egene a i e he apy and can imp o e he egene a i e
capaci y o mesenchymal s em cells wi h he ans e o espi-
a o y compe en mi ochond ia ha imp o e wound healing
[60]. The os eogenic di e en ia ion o mesenchymal s em cells
is impai ed unde in lamma o y condi ions due o mi ochon-
d ial dys unc ion and can be es o ed by ac i a ing he canna-
binoid ecep o I [61]. Changes in mi ochond ial me abolism a e
a c i ical mechanism o mac ophage unc ions du ing wound
healing. A subpopula ion o ea ly- s age wound mac ophages
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5 o 22
showed mi ochond ial ROS p oduc ion ha p omo es p ope
ascula iza ion; on he con a y, he la e phase is media ed by
mi ochond ial espi a ion and mi oho mesis [62]. E en mi o-
chond ial eplacemen he apy has been implemen ed in in i o
e iliza ion o a oid he ansmission o diseases. Recen ly, his
mi o he apy has ep esen ed an a ac i e pa adigm o he
ea men o ne ous sys em diso de s [63]. In addi ion, mi o-
chond ial ans e and ansplan a ion ha e been p oposed o
ea skin aging [64]. All o hese poin s could be conside ed in
he u u e o ea pe iodon i is.
2.2 | Rough Endoplasmic Re iculum
The endoplasmic e iculum (ER) is an in e connec ed ne wo k
o cis e nae ha can be co e ed by ibosomes ( ough endoplas-
mic e iculum RER) o no (smoo h endoplasmic e iculum
SER). The memb anes a e con inuous wi h he ou e nuclea
memb ane, and he cis e nal space is con inuous wi h he pe i-
nuclea space. SER is in ol ed in lipid syn hesis, p oduc ion
o s e oid ho mones, and de oxi ica ion. The unc ions o RER
include p o ein olding and ma u a ion o p o eins p oduced
by RER ibosomes and hei anspo o he Golgi appa a us.
Mo e han a hi d o all p o eins made in he cell en e he RER
lumen, old in a h ee- dimensional shape, and unde go a ious
pos - ansla ional modi ica ions ha include glycosyla ion and
disulphide bond o ma ion. Bo h p ocesses need he special mo-
lecula en i onmen o ER, di e en om he cy osol, wi h a
highe calcium concen a ion, essen ial o glycosyla ion, and
a mo e educing edox po en ial, essen ial o he o ma ion o
disulphide bonds [65]. This disulphide bond o ma ion, be ween
polypep ide chains, is assis ed by chape ones and in ol es he
ans e o wo elec ons p o ided by he enzyme p o ein di-
sulphide isome ase, in a edox p ocess [66]. ROS a e p oduced,
and i is es ima ed ha a ound 25% o ROS p oduc ion in he
endoplasmic e iculum is gene a ed by disulphide bonds du ing
oxida i e p o ein olding [67]. Gene ally, H2O2 is p oduced, and
25% o he oxygen used in he cell is es ima ed o be sp ead by
he endoplasmic e iculum [68]. In addi ion, o he mechanisms
a e in ol ed in he s ess o he endoplasmic e iculum, such as
NADPH oxidase 4, NADPH- P450 educ ase ac i i ies, and glu a-
hione (GSH), highligh ing he signi ican oles in he pa hogen-
esis o human diso de s [69]. Bu he p o ein- olded machine y
has a limi ed capaci y, and when i is o e whelmed, i p oduces
mis olded p o eins ha accumula e in cells su e ing RER s ess
[70, 71]. Du ing RER s ess, he ca e ully coo dina ed edox
sys em is dis up ed, causing he accumula ion o un olded p o-
eins wi h dis en ion o he RER lumen, inc eased ROS p oduc-
ion, and deple ion o in acellula GSH by oxida ion [72]. Some
dis u bances can p omo e his accumula ion, such as nu ien
dep i a ion, hypoxia, mu a ed p o eins, and loss o calcium ho-
meos asis [73] (Box4).
The balance in p o ein- olding capaci y is essen ial, and when
mis olded p o ein inc eases, an un olded p o ein esponse
(UPR) s a s o emedy he si ua ion. This is an essen ial adap-
i e in acellula signaling pa hway igge ed by me abolic
s ess, oxida i e s ess, and in lamma ion [74]. Using he mea-
su emen o RER edox s a us and UPR, a ious s esso s show
a comp omised RER p o ein oxida ion ha con ibu es o dia-
be es, neu odegene a ion, and cance [82]. When his adap i e
esponse is inadequa e o con ol ER s ess, he cell dea h p o-
cess is ac i a ed, some imes in ol ing a mi ochond ial apop o ic
mechanism pa hway [83]. Indeed, he mos impo an o ganelle
ela ed o RER is he mi ochond ion. The e a e mi ochond ia-
associa ed memb ane egions ha e e sibly bind RER o mi-
ochond ia. They a e in ol ed in he ansac ion (exchange)
o lipids, calcium homeos asis, au ophagy, apop osis, and how
m DNA is eplica ed and seg ega ed [84]. The ER is he mos
signi ican calcium s o age si e, wi h an in e ac ion wi h he mi-
ochond ia [75].
Pe iodon i is, as an in lamma o y ch onic disease, has been
associa ed wi h RER s ess highligh ing di e en aspec s [76].
Pe iodon al issues a e highly dynamic and need an adequa e
unc ion o all cellula mechanisms and especially he app op i-
a e syn hesis o p o eins. The p oduc ion o collagen and cellula
di e en ia ion a e essen ial o main ain pe iodon al homeos a-
sis. When human gingi al ib oblas s a e exposed o RER s ess,
hey exhibi p o ein deg ada ion and induced cell dea h [77].
Also, he induc ion o gingi al ib osis ound in d ug- induced
gingi al o e g ow h migh be a consequence o ER s ess [78].
P. gingi alis LPS ac i a es ER s ess in human pe iodon al lig-
amen cells [79] and is in ol ed in al eola bone eso p ion in
expe imen al pe iodon i is [80]. Recen ly, h ough machine
lea ning me hods, h ee po en ial bioma ke genes in ol ed in
RER s ess, SERPINA1, ERLEC1, and VWF, ha e been iden i-
ied in pe iodon i is [81].
BOX 4 | Essen ial aspec s o ough endoplasmic e iculum.
Gene al aspec s Pe iodon al aspec s
• I has unc ions in p o ein olding and ma u a ion [65].
• I in ol es a educed edox po en ial en i onmen [66].
• I p oduces ROS [67].
• ROS and un olded p o eins inc ease RER s ess [72].
• An un olded p o ein esponse (UPR) s a s o emedy he
si ua ion [74].
• I is ela ed o mi ochond ia h ough memb ane
mi ochond ia egions associa ed wi h mi ochond ia [75].
• S ess om RER ela ed o pe iodon i is [76].
• Gingi al ib oblas s exposed o RER s ess show p o ein
deg ada ion and cell dea h [77].
• D ug- induced gingi al o e g ow h migh be a
consequence o ER s ess [78].
• P. gingi alis LPS ac i a es ER s ess in human pe iodon al
ligamen cells [79] and p oduces al eola bone eso p ion
[80].
• Bioma ke genes in ol ed in RER s ess ha e been
iden i ied in pe iodon i is [81].
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6 o 22 Jou nal o Pe iodon al Resea ch, 2025
2.3 | Pe oxisomes
The pe oxisome is a poo ly known o ganelle ha can induce
diseases called pe oxysomopa hies ela ed o neu odegene a i e
diseases, such as Alzheime 's disease and mul iple scle osis. I is
a single memb ane- bounded o ganelle p esen in all euka yo ic
cells ha a y in size, numbe , and unc ions, adap ing o me -
abolic equi emen s and en i onmen al condi ions. I con ains
some oxidases ha p oduce H2O2 using oxygen and ca alase and
play key oles in he syn hesis and u no e o complex lipids,
he educ ion o ROS, and oxida i e inju y [85]. The main unc-
ions a e he b eakdown o e y long chain a y acids h ough
be a oxida ion and hei ans e o mi ochond ia and he p o-
duc ion o plasmalogen, he mos abundan myelin phospho-
lipid [86]. Choles e ol, an essen ial lipid in euka yo ic cells, is
anspo ed among o ganelles mainly om he lysosome o he
pe oxisome. Pe oxisome gene al e a ions ha e an expec ed ole
in choles e ol anspo , and choles e ol accumula es in cells as
pa o he pe oxisomal diso de [87]. Pe oxisomes play a ole in
cellula ROS me abolism wi h he glu a hione an ioxidan as a
c ucial componen ha main ains edox homeos asis [88]. They
a e o en jux aposed wi h o he o ganelles, such as RER, mi o-
chond ia, and lipid d ople s, ha allow unc ional coope a ion
be ween o ganelles [89]. Apa om being a me abolic o ganelle,
i is in ol ed in immune diso de s, in lamma ion, and cance .
Polyunsa u a ed a y acids, as pe oxisomal lipid me aboli es,
a e p ecu so s o leuko ienes and esol ins as immune media-
o s. Pe oxisomal edox me abolism modula es cellula immune
signaling such as nuclea ac o kappa- ligh - chain- enhance o
ac i a ed B cells (NF- κB) ac i a ion. The e o e, hese aspec s
highligh he impo ance in he ac i a ion o inna e and adap-
i e immune cells linked o in lamma o y diseases [90] (Box5).
One o he mos s udied molecules ha induce he p oli e a ion
o pe oxisomes in cells is pe oxisome p oli e a o - ac i a ed e-
cep o s (PPARs). They a e nuclea ecep o p o eins ha unc-
ion as ansc ip ion ac o s ha egula e he exp ession o
genes. Th ee ypes o PPAR ha e been iden i ied, which egula e
cellula di e en ia ion, de elopmen , and me abolism (ca bohy-
d a e, lipid, p o ein), and umo p oduc ion [91]. Fu he mo e,
hey p omo e he exp ession o an ioxidan enzymes ha p o-
duce a educ ion in he concen a ion o ROS ha egula es he
cellula esponse o oxida i e s ess condi ions [93]. They a e
ela ed o me abolic synd ome, ca dio ascula disease, and can-
ce , and he use o speci ic agonis s/an agonis s has po en ial
he apeu ic use ulness in in ec ious diseases [92]. PPARs a e
ela ed o pe iodon i is as an in lamma o y disease due o he
abili y o modula e in lamma ion, inhibi he LPS- induced in-
lamma o y esponse, in luence bone me abolism, and could be
a mee ing poin wi h ela ed sys emic diseases [43].
2.4 | Au ophagy
The main cellula o ganelles in ol ed in he p oduc ion o di -
e en oxida i e molecules ha e been e iewed. Bu he cell
needs o elimina e he aul y molecules, o hose ha come om
ou side, o b eak down he no mal molecules o p oduce ene gy
in s a a ion si ua ions. Au ophagy is a deg ada ion pa hway
and a ecycling p ocess ha cleans up he cell, p ese es cellula
unc ionali y, and plays an impo an ole in he homeos asis o
cells (Box6).
The e o e, i plays an impo an ole in adap a ion o me a-
bolic demands, immuni y, in lamma ion, and i is ela ed o
innume able diseases, especially neu odegene a i e, in lamma-
o y diso de s, and cance [94]. Fou o ms o au ophagy ha e
been desc ibed: mac oau ophagy, mic oau ophagy, chape one-
media ed au ophagy, and c inophagy.
Mac oau ophagy engul s a po ion o he cy oplasm o an o gan-
elle wi h a hin memb ane, called a phagopho e, and hen o ms
a double memb ane o ganelle called an au ophagosome. This
au ophagosome uses o he lysosome and deg ades i s con en .
The p ocess in ol es he ac ion o mul iple p o eins encoded
by au ophagy- ela ed genes (ATG) [108]. A speci ic mac oau o-
phagy is called mi ophagy. Mi ophagy deg ades damaged and
supe luous mi ochond ia ha a e essen ial o main ain cellu-
la homeos asis. Dys egula ion o mi ophagy is a con ibu ing
ac o o he pa hogenesis o me abolic diseases [109]. Also, i
is an essen ial componen o mammalian de elopmen al and
di e en ia ion p ocesses, o ins ance, he elimina ion o pa e -
nal mi ochond ia om he e ilized egg [110]. Mic oau ophagy
in ol es he di ec engul ing o cy oplasmic ma e ial in o ly-
sosomes, excluding he in ol emen o au ophagosomes [111].
Chape one- media ed au ophagy is a selec i e o m ha modu-
la es he u no e o a speci ic pool o soluble cy osolic p o eins
ecognized by he con aining complex o hsc70. These iden i ied
p o eins a e a ge ed, engul ed, and deg aded by lysosomes.
I modula es glucose and lipid me abolism, DNA epai , cell
BOX 5 | Essen ial aspec s o pe oxisomes.
Gene al aspec s Pe iodon al aspec s
• They con ain oxidases ha p oduce H2O2 using oxygen
and ca alase [85].
• They play key ole in he syn hesis and u no e o
complex lipids, he educ ion o ROS, and oxida i e inju y
[86].
• They ha e an expec ed ole in choles e ol anspo [87].
• They a e in ol ed in immune diso de s, in lamma ion,
and cance [90].
• PPARs induce he p oli e a ion o pe oxisomes [91].
• They in luence bone me abolism [92].
• They could be a mee ing poin wi h he pe iodon al ela ed
sys emic diseases [92].
• They inhibi he LPS- induced in lamma o y esponse [92].
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7 o 22
ep og amming, and cellula esponse o s ess [112]. The leas
known deg ada ion p ocess is c inophagy. I con ols abno mal,
excess, o obsole e sec e o y g anules, main aining he p ope
in acellula pool o sec e o y g anules. I is conside ed a quali y
con ol checkpoin in he ma u a ion o sec e o y esicles. Some
human diso de s, such as insulin sec e ion in diabe es, ha e
been associa ed wi h de ec i e lysosomal clea ance o sec e o y
ma e ials [113].
Au ophagy is a selec i e p ocess inhibi ed o ac i a ed due o a
a ie y o in a- and ex acellula s imuli, depending on he ype
o cell, i s mic oen i onmen , nu ien s, and oxygen supply [95].
Nume ous da a ha e been published a guing o oxida i e s ess
as a main s imulus ha sus ains au ophagy [96]. ROS gene a ion
occu s mainly in mi ochond ia, RER, and cy osolic NADPH oxi-
dases, which a e in e ela ed and in luenced by exogenous ROS.
Mi ochond ia ep esen he main sou ce o ROS ha induce au-
ophagy as signaling molecules ha lead o ei he su i al o
cell dea h [114]. An inc ease in he le el o cellula ROS is also
known o igge mi ophagy [97]. I has been demons a ed by
measu ing he cellula con en o hyd ogen pe oxide and supe -
oxide ha he la e is co ela ed wi h he ex en o au ophagy
and he e o e is he majo ROS au ophagic egula o [115]. RER
s ess induces au ophagy in human gingi al ib oblas s h ough
a la ge numbe o au ophagic esicles and au ophagic ma ke s
such as Beclin- 1 and LC- 3 [101].
The c oss alk be ween au ophagy and oxida i e s ess modi ies
in lamma o y condi ions ha lead o he de elopmen o non-
communicable disease [98]. In pe iodon i is, di e en aspec s
ha e been s udied. The bone cells oxida i e s ess- induced au-
ophagy is egula ed h ough di e en pa hways such as ROS/
FOXO3, ROS/AMPK, ROS/Ak /mTOR, and ROS/JNK/c- Jun
ha in luence bone o ma ion and eso p ion [116]. The adap-
a ion o biomechanical loading in human pe iodon al ligamen
ib oblas s in ol ed au ophagic mechanisms [117]. The ole o
au ophagy in pe iodon al disease has been known due o he
in e ac ion wi h pe iodon al in lamma ion media ed by RER
s ess [102]. Lowe m DNA le els, inc eased ATG5, LC3- II,
lowe PDK2 p o ein le els, and mi ochond ial des uc ion ha e
been shown in gingi al pe iodon i is ib oblas s [53]. Au ophagy
inc eases in lamma ion in pe iodon i is wi h he p oduc ion
o cy okines media ed by mTOR inac i a ion [103]. Pe iphe al
blood mononuclea cells om pe iodon i is pa ien s show an in-
c eased le el o au ophagic gene exp ession and a high le el o
mi ochond ial ROS [104].
Lysosomes a e essen ial o ganelles o au ophagic deg ada ion.
These can deg ade ex acellula ma e ial by endocy osis o in-
acellula ma e ial by au ophagy. Also, o he oles in nu ien
sensing and me abolic adap a ion ha e a majo ole in cellula
physiology [99]. They a e single memb ane- bound sphe ical es-
icles ha con ain di e en enzymes capable o diges ing many
kinds o molecules. As in he s omach, he enzymes a e ac i a ed
in an op imal acidic en i onmen (pH 4.5–5.0) due o pumping
in p o ons (H+ ions) h ough p o on pumps and chlo ide ion
channels. Lysosomes mus pe o m hei ac i i y h ough he
endosomal- au ophagic- lysosomal sys em in which hey use
o au ophagosomes o in a mic oau ophagy and chape one-
media ed au ophagy p ocess. Lysosomal enzymes and mem-
b ane p o eins a e syn hesized in he RER and con olled by
ansc ip ion ac o s. These ansc ip ion ac o s ac as a mas e
egula o o lysosomal unc ion, a e ac i a ed by ROS, and go -
e n cell homeos asis in esponse o oxida i e s ess [118], also
egula e cellula s ess unde s a a ion and ER s ess condi-
ions [119]. E en o an an ioxidan , he sul o aphane induced
i s p o ec ion h ough a mode a e inc ease in ROS [120]. When
one o he genes ha con olled hese enzymes is mu a ed, an
accumula ion o a speci ic subs a e p oduces lysosomal s o age
diseases.
These include neu odegene a i e diso de s, ca dio ascula
disease, cance , and age- ela ed diseases [100]. The hype in-
lamma o y esponse in gingi al epi helial cells in diabe es-
associa ed pe iodon i is in ol ed a lysosomal dys unc ion due o
comp omised acidi y [105].
BOX 6 | Essen ial aspec s o au ophagy.
Gene al aspec s Pe iodon al aspec s
• Au ophagy is a cellula deg ada ion pa hway and a
ecycling p ocess [94].
• I depends on ex acellula s imuli, cell ype,
mic oen i onmen , nu ien s, and oxygen supply [95].
• Oxida i e s ess as he main s imulus ha sus ains
au ophagy [96].
• Mi ochond ia and RER ROS induce au ophagy [97].
• I is in ol ed in cance , ca dio ascula disease, obesi y,
and Type II diabe es [98].
• Lysosomes a e essen ial o ganelles o au ophagic
deg ada ion [99].
• Lysosomal s o age diseases a e ela ed o ROS [100].
• RER s ess induces au ophagy in human gingi al
ib oblas s and os eoblas s [101].
• Au ophagy in pe iodon al disease is media ed by RER
s ess [102].
• Au ophagy inc eases in lamma ion in pe iodon i is wi h
he p oduc ion o cy okines [103].
• Pe iphe al blood mononuclea cells om pe iodon i is
pa ien s show an inc eased le el o au ophagic gene
exp ession [104].
• Gingi al epi helial cells show lysosomal dys unc ion in
pe iodon i is [105].
• Ca hepsin C is associa ed wi h se e e pe iodon i is p esen
in Papillon–Le e e synd ome [106].
• Ca hepsin K, he mos po en mammalian collagenase,
plays a special ole in bone eso p ion [107].
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8 o 22 Jou nal o Pe iodon al Resea ch, 2025
The majo class o hyd oly ic lysosome enzymes is ca hepsins; in
humans, 11 cys eine ca hepsins ha e been desc ibed [121]. The
mu a ed gene o one o hese ca hepsins, ca hepsin C, is associ-
a ed wi h se e e pe iodon i is p esen in he Papillon–Le e e
synd ome. The p oduc ion o a ecombinan ca hepsin C p o ein
by a baculo i us sys em in insec cell cul u es can es o e lyso-
somal unc ion [106]. Ca hepsin K is he mos po en mamma-
lian collagenase, which is highly exp essed in os eoclas s and
has a special ole in bone eso p ion [107]. Fu he mo e, lyso-
somes a e essen ial in lipid deg ada ion, especially in he con ol
o choles e ol homeos asis [122].
2.5 | Aging
Aging is he mos impo an cha ac e is ic o ou popula ion
ha is de e minan o he heal h sys em. I is a uni e sal p ocess
p esen in all mul icellula o ganisms caused by he de e io a-
ion o he no mal unc ion o he cells. Cells lose hei abili y
o p oli e a e and eplace damaged cells accumula ed o e ime,
in a p ocess known as cellula senescence, which causes o gan-
ismal aging and dys unc ion [123]. Biological aging is he esul
o mul iple cooccu ence hallma ks, which encompass a wide
ange o biological p ocesses, wo o hem ela ed o pe iodon i-
is, ch onic in lamma ion, and dysbiosis [124], whose p esence
sugges s an inc eased isk o pe iodon i is [125]. The links be-
ween aging and oxida i e s ess we e i s p oposed in 1956
[126]. Oxida i e s ess damages cell physiology due o an exces-
si e amoun o ROS ha a ec s di e en molecules (Box7).
All o ganisms mus deal wi h many en i onmen al dange s
ha h ea en hei su i al; i ac i a es in lamma ion, a sel -
p o ec ion machine y ha includes inna e and adap i e e-
sponse, which a e bo h igh ly in luenced by oxida i e s ess
[135]. The adap i e immune sys em esponds o a speci ic an-
igen, and he inna e immune sys em esponds quickly o a di-
e se se o mic obial and s e ile insul s. The i s s ep is hen
o ecognize h ea s h ough he pa e n ecogni ion ecep o s
(PRRs) ha a e sensi i e o pa hogen- and damage- associa ed
pa e ns (PAMPs and DAMPs). PAMPs include mic obial cell
wall componen s, bac e ial and i al DNA, as well as ungal sig-
na u es. DAMPs a e hos - de i ed and include molecules com-
ing om inju ed o dying cells, as well as molecules eleased
upon inju y and li es yle molecula pa e ns accumula ed o e
ime, such as choles e ol o oxidized low densi y lipop o ein
[136]. PRR ac i a ion induces NF- κB ac i a ion o in lamma o y
genes such as TNF and IL- 6 and he assembly o in lammasome
ha d i es caspase, IL- 1β and IL18 p oduc ion and py op o ic
cell dea h [127]. Recen li e a u e p o ides da a ha ROS a e
in eg al o he ini ia ion and p opaga ion o in lammasome sig-
naling p omo ing he immune esponse [137]. One o he mos
s udied in lammasome, namely NLRP3, depends on ROS p o-
duc ion, and i has been demons a ed ha ROS sca enge s im-
pai i s assembly and ac i a ion [128]. So, he in lammasome is
an essen ial pa o he inna e immune sys em, bu i s con inued
ac i a ion can be ha m ul o an o ganism.
An aging p ocess ha includes con inuous oxida i e s ess
can be de imen al o cellula homeos asis [138]. Redox s a us
plays a c ucial ole in egula ing cellula senescence, whe e pe -
sis en ly ele a ed oxida i e s ess p oduces a signi ican inc ease
[129]. Supp ession o NLRP3 p e en s age- associa ed changes in
he hea , p ese es ca diac unc ion, and inc eased li espan
[130]. ROS p oduc ion has a double e ec . Mild ele a ion leads
o adap a ion o ex e nal insul s and p e en s age- dependen
decline. Pe sis en oxida i e s ess is ela ed o in lammaging
ha is ha m ul and ela ed o aging diseases [139]. The ole o
he in lammasome in o al diseases and he de elopmen and
he apy o pe iodon i is ha e been widely discussed. I has eg-
ula o y unc ions in pe iodon al cells, especially in os eoclas s
and os eoblas s, and some d ugs ha e po en ial o ea ing pe i-
odon i is [131, 140]. In pe iodon i is pa ien s, he concen a ion
o NLRP3 inc eases in bo h se um and sali a [132].
Aging p oduces impai ed mi ochond ial unc ion and a b eak-
down o mi ocellula communica ion; he e o e, s a egies o
imp o e mi ochond ial unc ion can inc ease li espan [141]. In
senescen cells, lysosomes con ain lipo uscin, a sou ce o hy-
d oxyl adicals, which show dec eased au ophagic deg ada ion
capaci y, enhanced oxida i e s ess, and mi ochond ial dys unc-
ion [142]. Mi ochond ial adap a ions a e associa ed wi h bo h
acu e and ch onic in lamma ion by es ic ing a y acid oxida-
ion ha induces op imal ac i a ion o he NLRP3 in lammasome
[143]. Damaged mi ochond ia and hei oxidized m DNA signal-
ing eleased by nec o ic cells can be sensed by TLR ecep o s
and a e associa ed wi h ac i a ion o NLRP3 [40]. Also, usion,
ission, molecula biogenesis, and K ebs cycle molecules, such
as succina e, uma a e, and ci a e engage in p ocesses ela ed
BOX 7 | Essen ial aspec s o aging.
Gene al aspec s Pe iodon al aspec s
• Aging is ela ed o in lamma ion and oxida i e s ess
[124].
• Immune ac i a ion includes in lammasome ac i a ion
ha d i es IL- 1β, IL18, and py op o ic cell dea h [127].
• NLRP3 in lammasome ac i a ion depends on ROS
p oduc ion and is ac i a ed in aging [128].
• Aging p oduces mi ochond ial impai men [129].
• Supp ession o NLRP3 p e en s age- associa ed changes in
he hea [130].
• Oxidized m DNA ac i a es NLRP3 [40].
• The in lammasome has a egula o y unc ion in
pe iodon al cells [131].
• NLRP3 concen a ion inc eases bo h in se um and sali a
in pe iodon i is [132].
• m DNA mu a ions a e p esen in gingi al and ca diac
issues in pe iodon i is [24].
• Gingi al ib oblas s in pe iodon i is acqui e a senescen
pheno ype p oduced by oxida i e s ess [133].
• Excess ROS p oduc ion, mi ochond ial dys unc ion, and
de icien mi ophagy a e p esen in pe iodon i is [134].
16000765, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/j e.70016 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [21/07/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
9 o 22
o inna e and adap i e immune cells [17]. Analysis o m DNA
mu a ions shows mul iple a ian s sha ed by gingi al and ca -
diac issues in pe iodon i is pa ien s, and some o hem esul ed
om oxida i e o ces [24]. Gingi al ib oblas s om pe iodon i-
is pa ien s acqui e a senescen pheno ype p oduced by oxida i e
s ess- induced DNA and mi ochond ial damage [133]. Excessi e
ROS p oduc ion, mi ochond ial dys unc ion, and de icien mi o-
phagy a e some o he hallma ks o cellula senescence in pe i-
odon i is and ype II diabe es melli us [134].
3 | Exogenous Sou ces
3.1 | Nu i ion
Nu ien s a e sou ces o ene gy; he e o e, hei a ailabili y di-
ec ly in luences he oxida i e s a us o each o ganism. I he e
is an excess o any o hem, i will accumula e as a ese es in
adipose issue o la e use, causing obesi y, which is associa ed
wi h some diseases. I he e is a sho age, hey can s imula e ce -
ain heal h mechanisms, and in ex eme si ua ions, o ganisms
use hei own s uc u al molecules o ob ain ene gy h ough au-
ophagy (Box8).
3.1.1 | Obesi y
One o he mos widesp ead cha ac e is ics o ou socie y is
he abundance o nu ien s ha accumula e in adipose issue
unde d ople s o iglyce ides and inally con ibu e g ea ly
o he p oduc ion o obesi y. Obesi y is de ined as body mass
index (BMI) g ea e han 30 kg/m2. The pe cen ages o obese
and o e weigh adul s a e expec ed o inc ease o 50% by 2030
[156]. Excess ene gy in ake impai s mi ochond ial unc ion
wi h educed ATP syn hesis due o ROS accumula ion mainly
in me abolically ac i e issues such as adipose issue, muscle,
and li e [157]. Adipose issue plays an impo an ole as a eg-
ula o o ene gy homeos asis as an ene gy s o age and wi h en-
doc ine unc ion [144]. Obesi y is associa ed wi h inc eased ROS
p oduc ion [158]. The excess o nu ien s does no inc ease mi-
ochond ial oxida i e phospho yla ion in adipocy es bu a he
a gene a ion o in acellula H2O2 om nico inamide adenine
dinucleo ide phospha e oxidase (NOX) ha causes he exp es-
sion o chemo ac ic ac o and p omo es an in lamma o y phe-
no ype. These e ec s o NOX a e dependen on hei localiza ion
in lipid a s ha inc ease ROS p oduc ion, in acellula NF- κB
ac i a ion, and chemo ac ic signaling. I appea s ha adipocy e
NOX- de i ed H2O2 is essen ial o i s physiological condi ion
and may ini ia e adipose in lamma ion [145]. Obesi y is cha -
ac e ized by an inc easing popula ion o mac ophages ha
exp ess high le els o NOX and excess nu ien s ha p oduce
a d i e owa d p oin lamma o y pola iza ion [146]. These in-
lamma o y mac ophages educe he p oduc ion o adiponec in
by adipocy es in a dose- dependen manne by exogenous H2O2
[159]. Diminished adiponec in p oduc ion con ibu es o highe
NOX exp ession and ROS p oduc ion [160]. In e es ingly, mac-
ophages NOX exhibi a ime- dependen me abolic pheno ype
du ing die - induced obesi y: an 8- week p o ec i e e ec can be
obse ed while a e 16 weeks a de imen al e ec occu s wi h
no bene i [161]. The s o age o iglyce ides in adipocy es de-
elops a hype ophy ha in e e es wi h asco ba e and oxygen-
dependen disul ide bonding and p o ein olding in he RER
lumen, RER s ess, and a maladap i e UPR [147]. Addi ionally,
mi ochond ial dys unc ion due o hype ophy educed lipoly-
sis, inc eased iacylglyce ol syn hesis, and in lamma o y cy-
okine p oduc ion, dec eased insulin sensi i i y, and inc eased
ROS p oduc ion [162].
A posi i e associa ion be ween obesi y and pe iodon i is was
ound ega dless o coun y o age in me a- analysis s udies
[150, 163]. Some da a sugges ha obesi y is associa ed wi h os e-
opo osis, indica ing a nega i e impac o obesi y on bone quali y
and in he jawbone [164]. Obesi y- associa ed bone emodeling
is ela ed o hype in lamma ion, immune dys egula ion, and
mic obial dysbiosis in pe iodon i is [151]. Animal expe imen s
show a dec ease in he a io o educed/oxidized glu a hione
in obesi y [165]. In human s udies, an inc ease in pe iodon al
oxida i e s ess in obese pa ien s has been epo ed, associa ed
wi h clinical a achmen loss [152]. Sys ema ic e iews o he li -
e a u e showing he e ec s o obesi y on nonsu gical pe iodon-
al he apy a e s ill con o e sial. An in e io healing esponse
in pa ien s wi h high body mass index has been epo ed [166],
BOX 8 | Essen ial aspec s o nu i ion.
Gene al aspec s Pe iodon al aspec s
• Adipose issue plays an impo an ole as a egula o o
ene gy, Homeos asis, and as an ene gy depo [144].
• Nu ien s excess gene a es in acellula H2O2 om NOX
and ini ia e adipose in lamma ion [145].
• Obesi y inc eases he popula ion o mac ophages wi h a
high le el o NOX [146].
• The s o age o iglyce ides in adipocy es de elops RER
s ess [147].
• Speci ic nu ien s, die , and ime can in luence he
oxida i e s a us [15].
• In e mi en as ing educes oxida i e s ess [148].
• Calo ic es ic ion amelio a es in lamma ion due o aging
and educes oxida i e s ess [149].
• The e is a posi i e associa ion be ween obesi y and
pe iodon i is [150].
• Obesi y is associa ed wi h bone emodeling and is ela ed
o pe iodon i is [151].
• An inc ease in pe iodon al oxida i e s ess in obese
pa ien s is associa ed wi h clinical a achmen loss [152].
• The e exis s a signi ican nega i e associa ion be ween
adhe ence o he Medi e anean die and pe iodon i is
[153].
• The oxida i e balance sco e is associa ed wi h
pe iodon i is [154].
• Fas ing egimens ha e shown in pe iodon i is pa ien s
lesse bone loss [155].
16000765, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/j e.70016 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [21/07/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
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